Yonsei Med J.  2009 Jun;50(3):322-330. 10.3349/ymj.2009.50.3.322.

Epigenetic Regulation of Cytokine Gene Expression in T Lymphocytes

Affiliations
  • 1Department of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea. imsh@gist.ac.kr

Abstract

The developmental program of T helper and regulatory T cell lineage commitment is governed by both genetic and epigenetic mechanisms. The principal events, signaling pathways and the lineage determining factors involved have been extensively studied in the past ten years. Recent studies have elucidated the important role of chromatin remodeling and epigenetic changes for proper regulation of gene expression of lineage-specific cytokines. These include DNA methylation and histone modifications in epigenomic reprogramming during T helper cell development and effector T cell functions. This review discusses the basic epigenetic mechanisms and the role of transcription factors for the differential cytokine gene regulation in the T helper lymphocyte subsets.

Keyword

Epigenetics; cytokine; T lymphocytes; gene regulation

MeSH Terms

Animals
Cytokines/metabolism
Epigenesis, Genetic/*genetics
Gene Expression Regulation/genetics/physiology
Humans
T-Lymphocytes/*metabolism

Figure

  • Fig. 1 Diversification of naïve CD4 + T helper cells into various effector T helper cell lineages. Upon antigenic stimulation, naïve CD4 + T cells can be differentiated into diverse T helper cell subsets like Th1, Th2, Th17 and Treg. From in vitro and in vivo studies, instructive cytokines and transcription factors which are specific for each effector lineage were identified. In the early initiation stage, the unique signal transducer and activator of transcription (STAT) is activated by the environmental cytokine signals which leads to induction of lineage master regulators. Transcription factors from each distinct subset activate and control the various downstream genes and this mechanism is further enhanced and stabilizes the lineage commitment with epigenetic modification by specific stimuli and the action of transcription factors. As a result, effector cytokines and modulators can be released from each CD4 + T helper cell subsets and these further regulate immune responses accordingly to antigens.

  • Fig. 2 Epigenetic modifications in T helper cells. Histone modifications and DNA methylation are two major epigenetic mechanisms which governs gene expression in mammalian cells. First, DNA methylation is detected from the 5-cytosine of CpG dinucleotides or CpG islands which is generally associated with the mechanism of gene silencing. Posttranslational modification of histone molecules occurs mainly at H4 or H4 tails. Histone tails are easily modified by the external stimuli and consist of various types of modifications such as acetylation, methylation, phosphorylation, and sumoylation. Among these, acetylation and methylation on lysine residues are well known representative modifications during T helper cell differentiation. Level of acetylation and lysine 4 methylation of Histone H3 and H4 are generally linked with active and accessible state of gene regulation while methylation of lysine 9 and 27 are well known marks of silent or inactive gene regulation.


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